A 3.5.2 Parkinson s Disease and related disorders 10 November 2016 Marinela Vavla marinela.vavla@kcl.ac.uk
Learning objectives Basal ganglia: components and localization (inter)connections and functions Parkinson s Disease (and related motor disorders) Clinical presentation of PD Risk factors Molecular basis of PD Neuropathology/neurodegeneration (pathways) Treatment
Anatomy of the Basal Ganglia Basal Ganglia: CAUDATE STRIATUM PUTAMEN NUCLEUS ACCUMBENS GLOBUS PALLIDUS (GPe and GPi) SUBTHALAMIC NUCLEUS (STN) SUBSTANTIA NIGRA (SNpc and SNpr)
Nucleus Accumbens See n. 17. Tamraz and Comair, Atlas of regional anatomy of the Brain using MRI functions
Anatomy of the Basal Ganglia
More Basal Ganglia
Basal Ganglia Circuitry INPUTS Cortex (Glu) Intralaminal nuclei of thalamus SN in the midbrain (DA) Raphe nuclei (Serotonine) INTERCONNECTIONS Striatum Striato Nigral Nigro Striatal GP Pallido Subthalamic Subthalamic Pallidal Striato Pallidal OUTPUTS (From Gpi and SNpr) STN Ventral Anterior Nucleus
A Corticostriatal Thalamocortical Motor Circuit D 2 D 1 SNc
Direct pathway Putamen GPi, SNr Reduce output from GPi (GABA) Thalamus disinhibited Allows movement (cortex) Malfunction PD Bradykinesia Indirect pathway Putamen ( ) GPe ( ) STN (+) GPi Net output from GPi GABA Inhibits thalamus Inhibits movement (cortex) Malfunction HD/Chorea Basal Ganglia Circuitry
Relationship between the centre surround organization of the Gpi to inputs from the Striatum and STN.
What do the Basal Ganglia do? Motor preparation Action selection Reward based learning Exploratory behaviour Goal oriented behaviour Timing Action gating
Motor Disorders Hypokinetic disorders (PD) Akinesis Bradykinesis Hyperkinetic disorders (HD, HEMIBALLISMUS) Dyskinesis Athetosis, Ballism, Chorea, Dystonia
SNpc: PD Putamen: Dystonia Striatum (caudate and putamen): HD/Chorea STN, GPi: Hemiballism SNpr: Saccades/Involuntary eye movements Cortico striatal pallidalthalamic: Tourette, OCD. Damage to the BG
Parkinson s Disease
Dr James Parkinson (1755 1828)
Definition of PD Involuntary tremulous motion with lessened muscular power, in parts not in action and even when supported with a propensity to bend the trunk forwards and to pass from walking to a running pace. Termed Parkinson s Disease by Charcot
Presentation of PD: cardinal symptoms Tremor Bradykinesia Rigidity & Postural Instability
Constant Levels of Dopamine are Vital for Normal Movement Striatum Excitatory cortical input Dopaminergic regulatory input Substantia nigra Basal ganglia In the brain, constant levels of dopamine are required to Regulate cortical excitation of striatal neurons Stabilize the firing rate and excitability of striatal neurons Modulate plasticity of striatal neurons (long term potentiation) Normal motor function Olanow et al, 2006
Parkinson s Disease PD is characterized of loss of dopaminergic neurons in the SNpc.
Why/How does all this happen? Structure Function Pathology
Many Years Ago... PD was the first example of brain disorder resulting from a deficiency of a neurotransmitter Mid 1950s A. Carlson showed that 80% of the brain s DA is in the basal ganglia. O. Horynekiewict found that the brain of patients with PD are deficient in DA in the striatum and most severely in the putamen. Early 1960s PD was shown to result largely from the degeneration of the DAergic neurons in the SNpc. W. Brikmayer and O. Horynekiewict found that i.v L DOPA could provide a dramatic (but brief!) reversal of symptoms G. Cotzias demonstrated that gradual increase in p.o. L DOPA could provide significant and continuous benefit to the PD symptoms.
Neuropathology Death of SNpc dopaminergic neurons Presence of Lewy body and Lewy neurites intracytoplasmatic inclusions Immunostaining with an antibody against synuclein reveals a Lewy body (black arrow) with an intensely immunoreactive central zone surrounded by a faintly immunoreactive peripheral zone (left).
Risk Factors Genetic factors Environmental toxins Agricultural toxins (Paraquat, Rotenone) Drugs of abuse (Amphetamine, Cocaine) MPTP(1 methyl 4 phenyl 1,2,3,6 tetrahydropyridine) Protein aggregation Oxidative stress Metals (Fe, Al, Mn, Cu) Age Gender Premotor features (olfactory dysfunction, constipation, depression/anxiety and REM sleep disorders)
Lill, 2016
Genetic factors Lubbe and Morris, 2014
Molecular Basis of Autosomal Dominant PD A synuclein SNCA: Regulates the neurotransmitter vesicle function at the presynaptic membrane due to its ability to bind and stabilize lipid bilayers and its enrichment in presynaptic terminals Mutations + gene dosage effect lead to α syn protofibril formation which aggregates in Lewy bodies and Lewy neurites Α syn toxicity may involve the leakage of DA from synaptic vesicles because of perforation of the vesicular membranes Might be implicated in impaired cellular autophagy LRRK2/Dardarin PARK8: Cytoplasmic protein which might be associated to intracell. membranes as outer mitochondria, ER and Golgi apparatus. Mutations identified in α syn+ LB pathology or tau+ neurofibrillary tangle pathology suggesting a possible common role in the phosphorylation/processing of these two proteins
Molecular Basis of Autosomal Recessive PD Parkin: Ubiquitinates proteins targeting them for proteosomal degradation, and also implicated in cellular autophagy Mutations lead to impairment in binding the putative substrates and/or loss of function Studies of Parkin k.o. mice suggest that Parkin loss of function may lead to mitochondrial dysfunction and oxidative stress PINK1 (PTEN induced kinase 1) Phosphorylates ser/thre residues on basic substrates Mutations lead to disruption of kinase activity affecting the mitochondrial function and incresing cellular susceptibility to stress (TRAP1, Omi/HtrA2) DJ 1 Present in the brain and pheripheral tissues. Present in the cytoplasm with a small pool associated with mitochondria. It is involved in the oxidative stress response by acting as a redox dependent chaperone ATP13A2 Encodes for a P type ATPase which maintains the ion gradient across the cell membrane Although it is still unclear, in vitro models have shown that wt ATP13A2 is localized in lysosomes. The mutated proteins were retained in the ER and degraded by the proteasome Mutations cause an early onset parkinsonism with pyramidal degeneration and dementia. It is suspected to be caused by proteasomal degeneration due to an overload of retained protein
Pathways to PD Potential pathogenic mechanisms in PD: Ubiquitin proteasomal dysfunction Mitochondrial dysfunction & Oxidative stress Autophagy impairment
Pathways to PD
Animal Models in PD Ideal or suitable animal model of PD Characterized by progressive and significant loss of DA neurons and the loss of some non DA neurons, with onset during adulthood. Mimicking the clinical manifestation of the human disease, including the motor phenotype that includes bradykinesia, rigidity, postural instability and resting tremor, with motor features being responsive to L DOPA therapy. Rodent and Primate models: have been useful to Dissect the disease mechanism Improve therapeutic outcomes Toxin based models 6 OHDA Rotenone Paraquat MPTP Genetic based models More attractive alternatives: Zebrafish (Danio rerio) Fruit fly (Drosophila melanogaster) Auran (Xenopus laevis) Nematode (Caenorhabditis elegans) Yeast (Saccharomyces cerevisiae) Pienaar et al., 2012, Le et al., 2014
DaTSCAN (FP CIT SPECT) SPECT imaging of membrane dopamine transporters. Detects degeneration of dopaminergic nigrostriatal pathway eg presynaptic Parkinsonian syndromes Normal commas Abnormal retreating commas and full stops Note the asymmetry of uptake characteristic of PD but cannot distinguish PD from other forms of presynaptic parkinsonism eg MSA PSP Caudate Putamen
Differential Diagnosis PARKINSONISM Tremor Tremor Rigidity Resting or Bradykinesia Postural Postural instability /gait difficulty TREMOR DISORDERS Essential tremor Dystonic tremor Parkinson s disease Multiple System Atrophy Progressive Supranuclear Palsy Drug induced Vascular Structural Toxins Infections Metabolic Degenerative Non degenerative
Not all PD Symptoms are due to Dopamine Degeneration GABA GLU Ach STN:subthalamic nucleus; GPi:globus pallidus interna; GPe:external segment; SNc:substantia nigra pars compacta; VTA:ventral tegamental area Lang & Obeso, 2004
Braak Staging of Lewy Bodies Braak H, et al. J Neurology. 2002;249(suppl 3):1432 1459.
Symtoms of Parkinson s disease PD AUTONOMIC Motor syndrome (MS) Untreated Bradykinesia Rigidity Tremor Micrographia Gait problems Treated Dyskinesias Fluctuations AUTONOMIC NON MOTOR SYMPTOMS COMPLEX Gastrointesinal Genitourinary Sleep Pain Sexual Function Cognition Apathy Fatigue Misclleaneous: Olfactory Diplopia Hyperhidrosis Weight Change Chaudhuri et al,lancet Neurology 2006
Dementia in PD Pathological findings in a PDD case (a) Amyloid β (A4) senile plaques and (b) tau positive neurofibrillary tangles in hippocampus (original magnification, x200) (c) α Synuclein stained neocortical Lewy bodies (d) hippocampal Lewy neurites
Downregulation of Synthesis and Release of Dopamine
Symptomatic Principles of therapy I Replacement of the missing neurotransmitter DA agonists, Symptomatic and Neuroprotective MAO B inhibitors Neurosurgical therapies Surgical ablation therapy (Pallidotomy, Thalamotomy) Deep Brain Stimulation Anti Oxidant therapy: neuroprotection in order to slow the progression
Principles of Therapy II Gene therapy: aims to protect and repair neuronal damage Gene targets include α syn and Parkin Locations SNpc and STN Cell based therapies Transplant of foetal ventral mesencephalic tissue BUT Ethical Issues (two human trials showed negative results, and thereby compromising (?) the entire concept of cell replacement approach. Alternative: use of embryonic stem cells or committed neural precursors
Summary BG consists of Striatum, GP, STN and SN BG is importantly connected to other brain regions via afferent and efferent projections, and also interconnections between individual BG nuclei Motor control is mediated via the direct and indirect pathways in the BG circuitry BG is implicated in motor and non motor functions Damage in different nuclei of the BG may cause different types of motor disorders: hypo /hyperkinetic disorders PD is presented with tremor, bradykinesias and rigidity. Other motor and non motor symptoms might be present PD is caused by formation of LBs and LNs in the SNpc DAergic neurons leading to neuronal death Genetic studies have contributed to a better understanding of molecular pathways leading to neurodegeneration Different animal models have been used to study PD enlightening the current knowledge on pathogenic mechanisms Treatments have a propensity to control symptoms, although none (?) can halt the PD progression